ABSTRACT ? PROJECT 3 Medications to treat acute lymphoblastic leukemia (ALL) are used for many other malignant and nonmalignant diseases, in adults and in children, but their use is associated with a high risk of adverse effects. Identifying the genetic and non-genetic risk factors (e.g. age, treatment arm) for these adverse effects is essential to improve use of these medications to minimize the morbidity and mortality of these agents for non-ALL patients as well as for improving outcomes in ALL. We have strong preliminary data that the risks of adverse effects of ALL chemotherapy are at least partly heritable, but there has been a lack of cohort-based, systematic genome-wide approaches to rigorously define these risk factors. In Project 3, our goal is to identify the genetic and non- genetic risk factors for the most important adverse effects of commonly used ALL medications in children and adults. An important characteristic of our Center is that we are studying cohorts of patients (~ 6600 children and ~ 600 adults) enrolled on front-line clinical ALL trials, rather than using a health-records based or case- control approach. Advantages to this approach include: elimination of bias in case/control selection; administration of therapy is uniform, controlled, and documented; standardized assessment across trials that uses a common system for grading type and severity of adverse effects; ascertainment of non-genetic risk factors that are used as covariates in all analyses; and cost effectiveness, in that patients with and without the phenotype are analyzed for multiple other adverse events. Also, many of the same patients (and DNA) studied for assessing risk factors for adverse effects (Project 3) are also studied for assessing treatment outcomes (Project 1) and drug sensitivity (Project 2). For the first time, we are using a common approach to both pediatric (COG and SJCRH) and adult (CALGB/Alliance and ECOG) pharmacogenomic studies. Using genome-wide interrogations (Core B), we will determine the host- and treatment-related risk factors for four serious adverse effects: osteonecrosis (primarily due to glucocorticoids), hepatotoxicity (primarily due to asparaginase and methotrexate), vincristine-induced neuropathy, and pancreatitis (primarily due to asparaginase) in the Center?s core clinical trials. We will perform primary discovery in the pediatric trials, test for validation in adult trials, and separately analyze the adult-only and the combined pediatric and adult cohorts. We use state-of-the-art computational tools to annotate and prioritize variants using a common pipeline (as in Projects 1 and 2, Core C) for the four primary phenotypes. The highest priority variants will be assessed in preclinical models, to determine the mechanisms by which the top genetic and non-genetic risk factors affect the risk of osteonecrosis, as an example phenotype. We will combine the risk factors for adverse effects identified in Project 3 with those identified in Projects 1 and 2 for antileukemic response to contribute to an overarching aim for the Center (Aim 1 of Core C): to form the foundation for an approach to more precisely assign patients to regimens that minimize adverse effects while maintaining desired antileukemic effects.